Dr. Daniel Goldstein has submitted a Mentored Clinical Scientist Development Award (K08) application. Dr. Goldstein is training in Cardiovascular Medicine at the University of Alabama at Birmingham (UAB) and will become an Instructor in the Department of Medicine in July 2000. His career objective is to become a physician-scientist caring for cardiac transplant recipients with a research emphasis in transplantation immunology. His proposal will investigate the molecular mechanisms of donor spleen cell induced transplantation tolerance. Since failed solid organ transplantation is largely due to transplant rejection and the side effects of chronic immunosuppression agents, there is a need to develop protocols that can induce transplantation tolerance. The hypothesis of the research plan is that donor splenic natural killer cells secrete transforming growth factor beta inducing graft reactive cells to undergo apoptosis by a tumor necrosis factor dependent mechanism thus prolonging transplant survival. This hypothesis will be tested in a murine skin transplant model through use of mice with targeted mutations and by infusion of defined spleen cell subpopulations. Further, in vitro allogeneic cytotoxicity studies will be performed using blocking antibodies, and viral transduction of donor spleen cells. The University of Alabama has considerable expertise in experimental immunology and transplantation. The Department of Medicine will ensure that Dr Goldstein receives adequate space and time to devote 80% of his effort towards the research proposal. The career development program, mentor and didactic courses are designed to allow Dr. Goldstein to become an independent investigator by the end of the award period.